Safe and effective anti CD154 antibodies for therapeutic intervention

描述(申请人提供)：在动物概念验证研究和初步临床试验中，都有大量数据表明CD154阻滞剂在治疗移植物抗宿主病、器官移植和自身免疫性疾病方面的潜在疗效。然而，早期临床试验中观察到的抗体毒性阻碍了CD154作为治疗药物的发展。 移植物抗宿主病是异基因造血干细胞移植的并发症。移植物抗宿主病仍然是大约50%移植后存活1年的患者死亡的主要原因。护理标准仅限于需要长期服用、效果适中且与显著副作用相关的药物。因此，对安全有效的药物有着巨大的未得到满足的需求和巨大的潜力。在移植物抗宿主病中的研究已经证明，抗CD154抗体可以作为一种预防措施，并且作为一种单一疗法是有效的，正如在NHP中所证明的那样，在NHP中，仅使用CD154组成的短程治疗可以实现永久的同种异体移植耐受。这一策略消除了类固醇和钙调神经磷酸酶抑制剂的使用，这两种药物都与许多副作用有关。CD154因此具有竞争优势，因为大多数其他正在开发的药物将需要与类固醇或钙调神经磷酸酶抑制剂进行某种形式的联合治疗。由于有效地诱导耐受，在固体器官移植的接受者中也存在类似的改善临床结果的机会。此外，几乎所有的自身免疫性疾病模型都可以用CD154治疗有效地改善，并观察长期缓解。我们将把GVHD和与移植相关的慢性排斥反应作为我们商业开发的第一个临床适应症。 现有研究强烈表明，CD154单抗Fc区的结构域与其毒性和治疗能力有关。当临床和回顾性观察到NHP的毒性时，对抗体进行了修饰；当这些修饰消除了NHP的毒性时，CD154作为耐受性抗体的效力也显著降低。因此，CD154作为一种治疗药物的开发计划停滞不前。在第一阶段的研究中，我们确定了在小鼠模型中测试的导致CD154安全有效版本的修饰。这项建议的目标是在这些观察的基础上，产生不同形式的人CD154抗体，保留CD154的有益耐受作用，同时极大地降低或消除毒性。不同形式的抗体将在NHP模型中进行安全性和有效性评估。NHP移植模型的成功概念验证将是创造一种新的治疗方法的基础，这可能对自身免疫性疾病的治疗和器官移植产生深远的影响。

DESCRIPTION (provided by applicant): In both animal proof of concept studies and preliminary clinical trials, there is ample data demonstrating the potential therapeutic benefits o CD154 blockade for treatment of GVHD, organ transplantation and autoimmune diseases. However, development of ¿CD154 as a therapeutic has been impeded by antibody toxicity observed in early clinical trials. GVHD is a complication of allogeneic Hematopoietic Stem Cell Transplantation (HSCT). GVHD remains a major cause of mortality in approximately 50% of patients who survive > 1 year post transplant. The standard of care is limited to drugs that need to be taken long term, work moderately well and are associated with significant side effects. There is therefore profound unmet need and significant potential for drugs that are safe and efficacious. Studies in GVHD have demonstrated that anti-CD154 acts as a prophylactic and is effective as a monotherapy as demonstrated in NHP where permanent allograft tolerance can be achieved using short courses of treatments comprised of ?CD154 alone. This strategy eliminates the use of steroids and calcineurin inhibitors both of which are associated with numerous side effects. ?CD154 thus has a competitive advantage as most other drugs in development will require some form of combination therapy with either steroids or calcineurin inhibitors. A similar opportunity for improved clinical outcomes due to effective induction of tolerance exists in recipients of solid organ transplants. Furthermore, virtually all autoimmune disease models can be effectively ameliorated with ?CD154 therapy, with long-term remission observed. We will target GVHD and chronic rejection associated with transplantation as our first clinical indication for commercial development. Existing studies strongly suggest that domains within the Fc region of the ?CD154 mAb contribute to its toxicity and therapeutic capacity. When toxicity was observed in the clinic and retrospectively in NHP, modifications were made to the antibody; while these modifications eliminated toxicity in NHP, the efficacy of ?CD154 as a tolerogenic antibody also was significantly reduced. As a result, development programs for ?CD154 as a therapeutic stalled. In Phase 1 studies we identified modifications that resulted in safe and efficacious versions of ¿CD154 as tested in murine models. The goal of this proposal is to build on those observations and generate variant forms of the ?human CD154 antibody that retain the beneficial tolerogenic effects of ?CD154 while greatly reducing or eliminating toxicity. Variant forms of the antibody will be evaluated for both safety and efficacy in NHP models. Successful proof of concept in NHP transplant models will be the basis for creating a novel therapeutic, which could have far-reaching impacts on the treatment of autoimmune diseases and organ transplantation.